Synthesis of alkynones via carbonylative Sonogashira coupling reactions catalyzed by Pd(II)-N-Heterocyclic carbene-pyridine complexes

ABSTRACT

This disclosure relates to N-substituted Pd(II)-N-heterocyclic carbene-pyridine complexes, methods of preparing the complexes, and methods of using the complexes in Sonogashira coupling reactions.

TECHNICAL FIELD

This document relates to N-substituted Pd(II)-N-heterocyclic carbene-pyridine complexes. The document also relates to use of the complexes in carbonylative Sonogashira coupling reactions to form alkynones.

BACKGROUND

Alkynyl ketones, or alkynones, have utility as synthetic intermediates, particularly for the synthesis of heterocyclic systems that can be used as precursors in the synthesis of anti-cancer and anti-fungal products. Alkynones have also found use in the polymer industry. A common route for the synthesis of these compounds is the carbonylative Sonogashira coupling reaction. The reaction is typically catalyzed by a palladium complex and a large excess of an amine base. High catalyst loading, for example, greater than 1 mol % of the palladium complex is often required. This can lead to higher costs and less efficient reactions.

Therefore, there is a need for a palladium complex that can catalyze a Sonogashira coupling reaction, in particular, a carbonylative Sonogashira coupling reaction, that has high catalytic activity, is stable, and requires low catalyst loading.

SUMMARY

Provided in the present disclosure is a compound of Formula (I):

wherein:

R¹ is selected from C₁-C₁₀ alkyl, C₅-C₁₀ cycloalkyl, aryl, and (C₁-C₃ alkylene)-aryl;

R² is selected from C₁-C₁₀ alkyl, C₅-C₁₀ cycloalkyl, aryl, and (C₁-C₃ alkylene)-aryl;

R³ is selected from C₁-C₁₀ alkyl, C₅-C₁₀ cycloalkyl, aryl, and (C₁-C₃ alkylene)-aryl;

n is 0, 1, 2, 3, 4, or 5;

m is 1 or 2; and

represents a single or double bond.

In some embodiments of the compound of Formula (I), R¹ is C₁-C₆ alkyl. In some embodiments, R¹ is selected from methyl, ethyl, propyl, isopropyl, and butyl. In some embodiments, R¹ is isopropyl.

In some embodiments of the compound of Formula (I), R² is selected from C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, and (C₁-C₃ alkylene)-aryl. In some embodiments, R² is selected from isopropyl, benzyl, and adamantyl.

In some embodiments of the compound of Formula (I), n is 0.

In some embodiments of the compound of Formula (I), m is 2. In some embodiments, ring A is

In some embodiments, the compound of Formula (I) is selected from:

Also provided in the present disclosure is a compound of Formula (II)

wherein:

R¹ is selected from C₁-C₁₀ alkyl, C₅-C₁₀ cycloalkyl, aryl, and (C₁-C₃ alkylene)-aryl;

R² is selected from C₁-C₁₀ alkyl, C₅-C₁₀ cycloalkyl, aryl, and (C₁-C₃ alkylene)-aryl; and

X is a halide.

In some embodiments of the compound of Formula (II), R¹ is C₁-C₆ alkyl. In some embodiments, R¹ is selected from methyl, ethyl, propyl, isopropyl, and butyl. In some embodiments, R¹ is isopropyl.

In some embodiments of the compound of Formula (II), R² is selected from C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, and (C₁-C₃ alkylene)-aryl. In some embodiments, R² is selected from isopropyl, benzyl, and adamantyl.

In some embodiments, the compound of Formula (II) is selected from:

Also provided in the present disclosure is a method of preparing a compound of Formula (I):

the method comprising reacting a compound of Formula (II)

with pyridine in the presence of a palladium catalyst, wherein:

R¹ is selected from C₁-C₁₀ alkyl, C₅-C₁₀ cycloalkyl, aryl, and (C₁-C₃ alkylene)-aryl;

R² is selected from C₁-C₁₀ alkyl, C₅-C₁₀ cycloalkyl, aryl, and (C₁-C₃ alkylene)-aryl.

In some embodiments of the method, R¹ is isopropyl.

In some embodiments of the method, R² is selected from isopropyl, benzyl, and adamantyl.

In some embodiments of the method, the compound of Formula (I) is selected from:

In some embodiments of the method, the palladium catalyst is palladium bromide.

Also provided in the present disclosure is a method of preparing an alkynone, the method comprising contacting an aryl halide and an alkyne with a compound of Formula (I) in the presence of a CO source.

In some embodiments of the method, the aryl halide is a compound having the formula:

wherein:

X is selected from F, Cl, Br, and I; and

R′ is selected from —H, —O—(C₁-C₃ alkyl), —NO₂, and —C(═O)—(C₁-C₃ alkyl).

In some embodiments of the method, wherein X is I.

In some embodiments of the method, the alkyne is a compound having the formula:

wherein R″ is selected from —H, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl, —O—(C₁-C₃ alkyl), aryl, (C₁-C₃ alkyl)-(C₃-C₆ cycloalkyl), and (C₁-C₃ alkyl)-aryl.

In some embodiments of the method, the alkyne is a compound having the formula:

wherein R′″ is selected from —H, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl, —O—(C₁-C₃ alkyl), aryl, (C₁-C₃ alkyl)-(C₃-C₆ cycloalkyl), and (C₁-C₃ alkyl)-aryl.

In some embodiments of the method, the alkynone is a compound having the formula:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the method, the compound of Formula (I) is selected from:

In some embodiments of the method, the compound of Formula (I) is present in an amount of about 0.01 mol % to about 1.0 mol %.

DETAILED DESCRIPTION

The present disclosure relates to N-heterocyclic carbene (NHC)-pyridine ligands and palladium-NHC-pyridine complexes. The palladium-NHC-pyridine complexes exhibit high catalytic activity and efficiency with low catalyst loading. For example, the palladium-NHC-pyridine complexes exhibit high catalytic efficiency in the synthesis of alkynones via carbonylative Sonogashira coupling reactions. In some embodiments, the coupling reaction is between an aryl halide or aryl dihalide with an aryl alkyne, alkyl alkyne, or dialkyne. The resulting alkynones can be useful precursors in the synthesis of anti-cancer and antifungal products. The alkynones can also be used in the polymer industry.

Reference will now be made in detail to certain embodiments of the disclosed subject matter. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter.

Definitions

In this disclosure, the terms “a,” “an,” and “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. The statement “at least one of A and B” has the same meaning as “A, B, or A and B.” In addition, it is to be understood that the phraseology or terminology employed in this disclosure, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section.

Values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (for example, 1%, 2%, 3%, and 4%) and the sub-ranges (for example, 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise.

The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range.

In the methods described in the present disclosure, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.

As used herein, “alkyl” means a branched, or straight chain chemical group containing only carbon and hydrogen, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl and neo-pentyl. Alkyl groups can either be unsubstituted or substituted with one or more substituents. In some embodiments, alkyl groups include 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).

As used herein, “alkylene” means a bivalent branched, or straight chain chemical group containing only carbon and hydrogen, such as methylene, ethylene, n-propylene, iso-propylene, n-butylene, iso-butylene, sec-butylene, tert-butylene, n-pentylene, iso-pentylene, sec-pentylene and neo-pentylene. Alkylene groups can either be unsubstituted or substituted with one or more substituents. In some embodiments, alkylene groups include 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).

As used herein, “cycloalkyl” means a non-aromatic cyclic ring system containing only carbon atoms in the ring system backbone, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Cycloalkyl may include multiple fused rings. Cycloalkyl may have any degree of saturation provided that none of the rings in the ring system are aromatic. Cycloalkyl groups can either be unsubstituted or substituted with one or more substituents. In some embodiments, cycloalkyl groups include 3 to 10 carbon atoms, for example, 3 to 6 carbon atoms.

As used herein, “aryl” means a mono-, bi-, tri- or polycyclic group with only carbon atoms present in the ring backbone having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10 ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclic array; wherein at least one ring in the system is aromatic. Aryl groups can either be unsubstituted or substituted with one or more substituents. Examples of aryl include phenyl, naphthyl, tetrahydronaphthyl, and 2,3-dihydro-1H-indenyl. In some embodiments, the aryl is phenyl.

As used herein, the term “heteroaryl” means a mono- or bicyclic group having 5 to 10 ring atoms, such as 5, 6, 8, 9, or 10 ring atoms, such as 5, 6, 9, or 10 ring atoms; wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S. Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrrolo[2,3-6]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-6]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-6]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzofuran, tetrahydroquinoline, and isoindoline. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.

As used herein, “heterocyclyl” means a 3-14 membered, such as 3-11 membered, such as 3-8 membered nonaromatic mono-, bi- or tricyclic group comprising at least one heteroatom in the ring system backbone. Bicyclic and tricyclic heterocyclyl groups may include fused ring systems, spirocyclic ring systems, and bridged ring systems and may include multiple fused rings. In some embodiments, heterocyclyls have one to four heteroatom(s) independently selected from N, O, and S. In some embodiments, heterocyclyls have one to three heteroatom(s) independently selected from N, O, and S. In some embodiments, heterocyclyls have one to two heteroatom(s) independently selected from N, O, and S. In some embodiments, monocyclic heterocyclyls are 3-membered rings. In some embodiments, monocyclic heterocyclyls are 4-membered rings. In some embodiments, monocyclic heterocyclyls are 5-membered rings. In some embodiments, monocyclic heterocyclyls are 6-membered rings. In some embodiments, monocyclic heterocyclyls are 7-membered rings. As used herein, “monocyclic heterocyclyl” means a single nonaromatic cyclic ring comprising at least one heteroatom in the ring system backbone. Examples of heterocyclyls include azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazolidinyl imidazolidinyl, and thiomorpholinyl. In some embodiments, the heterocyclyl is selected from azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and tetrahydropyridinyl. As used herein, “bicyclic heterocyclyl” means a nonaromatic bicyclic ring system comprising at least one heteroatom in the ring system backbone. Examples of bicyclic heterocyclyls include 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, and 2-azabicyclo[2.2.2]octane. As used herein, “spirocyclic heterocyclyl” means a nonaromatic bicyclic ring system comprising at least one heteroatom in the ring system backbone and with the rings connected through just one atom. Examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 2-oxa-6-azaspiro[3.3]heptane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 1,7-diazaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 1-oxa-8-azaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]decane.

Compounds of Formula (I)

Provided in the present disclosure is a compound of Formula (I)

wherein:

R¹ is selected from C₁-C₁₀ alkyl, C₅-C₁₀ cycloalkyl, aryl, and (C₁-C₃ alkylene)-aryl;

R² is selected from C₁-C₁₀ alkyl, C₅-C₁₀ cycloalkyl, aryl, and (C₁-C₃ alkylene)-aryl;

R³ is selected from C₁-C₁₀ alkyl, C₅-C₁₀ cycloalkyl, aryl, and (C₁-C₃ alkylene)-aryl;

n is 0, 1, 2, 3, 4, or 5;

m is 1 or 2; and

represents a single or double bond.

In some embodiments of the compound of Formula (I), R¹ is C₁-C₁₀ alkyl. In some embodiments, R¹ is C₁-C₆ alkyl. In some embodiments, R¹ is selected from methyl, ethyl, propyl, isopropyl, and butyl. In some embodiments, R¹ is isopropyl. In some embodiments, the C₁-C₆ alkyl group is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —NH₂, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₃-C₆ cycloalkyl, —O—(C₁-C₃ alkyl), (C₁-C₃ alkylene)-O—(C₁-C₃ alkyl), and aryl.

In some embodiments of the compound of Formula (I), R¹ is C₅-C₁₀ cycloalkyl. In some embodiments, R¹ is selected from cyclopentyl and cyclohexyl. In some embodiments, the C₅-C₁₀ cycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —NH₂, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₃-C₆ cycloalkyl, —O—(C₁-C₃ alkyl), (C₁-C₃ alkylene)-O—(C₁-C₃ alkyl), and aryl.

In some embodiments of the compound of Formula (I), R¹ is aryl.

In some embodiments of the compound of Formula (I), R¹ is (C₁-C₃ alkylene)-aryl. In some embodiment, R¹ is benzyl.

In some embodiments of the compound of Formula (I), R² is selected from C₁-C₁₀ alkyl, C₅-C₁₀ cycloalkyl, aryl, and (C₁-C₃ alkylene)-aryl. In some embodiments, R² is selected from isopropyl, benzyl, and adamantyl. In some embodiments, R² is isopropyl. In some embodiments, R² is benzyl. In some embodiments, R² is adamantyl.

In some embodiments of the compound of Formula (I), R² is C₁-C₁₀ alkyl. In some embodiments, R² is C₁-C₆ alkyl. In some embodiments, R² is selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. In some embodiments, R² is isopropyl. In some embodiments, the C₁-C₁₀ alkyl group is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —NH₂, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₃-C₆ cycloalkyl, —O—(C₁-C₃ alkyl), (C₁-C₃ alkylene)-O—(C₁-C₃ alkyl), and aryl.

In some embodiments of the compound of Formula (I), R² is C₅-C₁₀ cycloalkyl. In some embodiments, R² is selected from cyclopentyl, cyclohexyl, and adamantyl. In some embodiments, R² is adamantyl. In some embodiments, the C₅-C₁₀ cycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —NH₂, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₃-C₆ cycloalkyl, —O—(C₁-C₃ alkyl), (C₁-C₃ alkylene)-O—(C₁-C₃ alkyl), and aryl.

In some embodiments of the compound of Formula (I), R² is (C₁-C₃ alkylene)-aryl. In some embodiments, R² is selected from benzyl, —(CH₂)₂-aryl, and —(CH₂)₃-aryl. In some embodiments, R² is benzyl. In some embodiments, the C₁-C₃ alkylene group and the aryl group are each optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —NH₂, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₃-C₆ cycloalkyl, —O—(C₁-C₃ alkyl), (C₁-C₃ alkylene)-O—(C₁-C₃ alkyl), and aryl.

In some embodiments of the compound of Formula (I), R¹ is C₁-C₆ alkyl and R² is selected from C₁-C₆ alkyl, C₅-C₁₀ cycloalkyl, and (C₁-C₃ alkylene)-aryl. In some embodiments, R¹ is C₁-C₆ alkyl and R² is C₁-C₆ alkyl. In some embodiments, R¹ is isopropyl and R² is isopropyl. In some embodiments, R¹ is C₁-C₆ alkyl and R² is C₅-C₁₀ cycloalkyl. In some embodiments, R¹ is isopropyl and R² is adamantyl. In some embodiments, R¹ is C₁-C₆ alkyl and R² is (C₁-C₃ alkylene)-aryl. In some embodiments, R¹ is isopropyl and R² is benzyl.

In some embodiments of the compound of Formula (I), n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

In some embodiments, m is 1. In some embodiments, m is 1 and ring A is:

In some embodiments, m is 1, n is 0, and ring A is:

In some embodiments, m is 2. In some embodiments, m is 2 and ring A is:

In some embodiments, m is 2, n is 0, and ring A is:

In some embodiments, the compound of Formula (I) is selected from:

In some embodiments, the compound of Formula (I) is

In some embodiments, the compound of Formula (I) is

In some embodiments, the compound of Formula (I) is

Compounds of Formula (II)

Also provided in the present disclosure are compounds of Formula (II)

wherein:

R¹ is selected from C₁-C₁₀ alkyl, C₅-C₁₀ cycloalkyl, aryl, and (C₁-C₃ alkylene)-aryl;

R² is selected from C₁-C₁₀ alkyl, C₅-C₁₀ cycloalkyl, aryl, and (C₁-C₃ alkylene)-aryl; and

X is a halide.

In some embodiments of the compound of Formula (II), R¹ is C₁-C₁₀ alkyl. In some embodiments, R¹ is C₁-C₆ alkyl. In some embodiments, R¹ is selected from methyl, ethyl, propyl, isopropyl, and butyl. In some embodiments, R¹ is isopropyl. In some embodiments, the C₁-C₆ alkyl group is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —NH₂, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₃-C₆ cycloalkyl, —O—(C₁-C₃ alkyl), (C₁-C₃ alkylene)-O—(C₁-C₃ alkyl), and aryl.

In some embodiments of the compound of Formula (II), R¹ is C₅-C₁₀ cycloalkyl. In some embodiments, R¹ is selected from cyclopentyl and cyclohexyl. In some embodiments, the C₅-C₁₀ cycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —NH₂, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₃-C₆ cycloalkyl, —O—(C₁-C₃ alkyl), (C₁-C₃ alkylene)-O—(C₁-C₃ alkyl), and aryl.

In some embodiments of the compound of Formula (II), R¹ is aryl.

In some embodiments of the compound of Formula (II), R¹ is (C₁-C₃ alkylene)-aryl. In some embodiment, R¹ is benzyl.

In some embodiments of the compound of Formula (II), R² is selected from C₁-C₁₀ alkyl, C₅-C₁₀ cycloalkyl, aryl, and (C₁-C₃ alkylene)-aryl. In some embodiments, R² is selected from isopropyl, benzyl, and adamantyl. In some embodiments, R² is isopropyl. In some embodiments, R² is benzyl. In some embodiments, R² is adamantyl.

In some embodiments of the compound of Formula (II), R² is C₁-C₁₀ alkyl. In some embodiments, R² is C₁-C₆ alkyl. In some embodiments, R² is selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. In some embodiments, R² is isopropyl. In some embodiments, the C₁-C₁₀ alkyl group is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —NH₂, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₃-C₆ cycloalkyl, —O—(C₁-C₃ alkyl), (C₁-C₃ alkylene)-O—(C₁-C₃ alkyl), and aryl.

In some embodiments of the compound of Formula (II), R² is C₅-C₁₀ cycloalkyl. In some embodiments, R² is selected from cyclopentyl cyclohexyl, and adamantyl. In some embodiments, R² is adamantyl. In some embodiments, the C₅-C₁₀ cycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —NH₂, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₃-C₆ cycloalkyl, —O—(C₁-C₃ alkyl), (C₁-C₃ alkylene)-O—(C₁-C₃ alkyl), and aryl.

In some embodiments of the compound of Formula (II), R² is (C₁-C₃ alkylene)-aryl. In some embodiments, R² is selected from benzyl, —(CH₂)₂-aryl, and —(CH₂)₃-aryl. In some embodiments, R² is benzyl. In some embodiments, the C₁-C₃ alkylene group and the aryl group are each optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —NH₂, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₃-C₆ cycloalkyl, —O—(C₁-C₃ alkyl), (C₁-C₃ alkylene)-O—(C₁-C₃ alkyl), and aryl.

In some embodiments of the compound of Formula (II), R¹ is C₁-C₆ alkyl and R² is selected from C₁-C₆ alkyl, C₅-C₁₀ cycloalkyl, and (C₁-C₃ alkylene)-aryl. In some embodiments, R¹ is C₁-C₆ alkyl and R² is C₁-C₆ alkyl. In some embodiments, R¹ is isopropyl and R² is isopropyl. In some embodiments, R¹ is C₁-C₆ alkyl and R² is C₅-C₁₀ cycloalkyl. In some embodiments, R¹ is isopropyl and R² is adamantyl. In some embodiments, R¹ is C₁-C₆ alkyl and R² is (C₁-C₃ alkylene)-aryl. In some embodiments, R¹ is isopropyl and R² is benzyl.

In some embodiments of the compound of Formula (II), X is a halide. In some embodiments, X is selected from F, Cl, Br, and I. In some embodiments, X is Br.

In some embodiments, the compound of Formula (II) is selected from:

In some embodiments, the compound of Formula (II) is:

In some embodiments, the compound of Formula (II) is:

In some embodiments, the compound of Formula (II) is:

Method of Preparing Compounds of Formula (I) and Formula (II)

Also provided in the present disclosure are methods of preparing compounds of Formula (I) and Formula (II). In some embodiments, the method includes reacting a compound of Formula (II), such as a compound of Formula (II) as described in the present disclosure, with pyridine in the presence of a palladium catalyst, to form a compound of Formula (I). In some embodiments, the compound of Formula (I) is isolated. In some embodiments, the compound of Formula (I) is purified.

In some embodiments, the palladium catalyst is selected from the group consisting of palladium bromide, palladium chloride, palladium iodide, and palladium sulfate. In some embodiments, the palladium catalyst is palladium bromide.

In some embodiments, the compounds of Formula (I) are prepared according to the general scheme presented in Scheme 1, where R¹, R², and X are as described elsewhere in this disclosure.

In some embodiments, the method includes preparing a compound of Formula (II). In some embodiments, the method includes reacting a substituted 1H-benzo[d]imidazole with a substituted halide to form a compound of Formula (II). In some embodiments, the compound of Formula (II) is isolated. In some embodiments, the compound of Formula (II) is purified. In some embodiments, the compound of Formula (II) is isolated and purified prior to using in the method of preparing compounds of Formula (I).

In some embodiments, the substituted halide has the formula R¹—X, where R¹ and X are as described elsewhere in this disclosure.

In some embodiments, the compound of Formula (II) is prepared according to the general scheme presented in Scheme 2, where R¹, R², R³, X, m, and n are as described elsewhere in this disclosure.

In some embodiments, the methods of the present disclosure are used to prepare a compound of Formula (I), where the compound of Formula (I) is selected from

In some embodiments, the methods of present disclosure are used to prepare a compound of Formula (II), where the compound of Formula (II) is selected from

Methods of Preparing Alkynones

The compounds of Formula (I) of the present disclosure are useful as catalysts. For example, the compounds of Formula (I) can be used as catalysts for the synthesis of alkynones, including aryl alkynones and alkyl alkynones. In some embodiments, the compounds of Formula (I) are used as a catalyst in a carbonylative Sonogashira coupling reaction. In some embodiments, the carbonylative Sonogashira coupling reaction is between an aryl halide or aryl dihalide and an aryl alkyne, alkyl alkyne, or dialkyne. In some embodiments, the carbonylative Sonogashira coupling reaction is between an aryl bromide, aryl iodide, or aryl diiodide and an aryl alkyne, alkyl alkyne, or dialkyne.

In some embodiments, the alkynones of the present disclosure are prepared according to the general scheme presented in Scheme 3, where R—X can be an aryl halide, aryl dihalide, or vinyl halide, and R′—C≡C can be an aryl alkyne, alkyl alkyne, or dialkyne.

Thus, provided in the present disclosure is a method of preparing an alkynone, the method including contacting an aryl halide, aryl dihalide, or vinyl halide and an alkyne with a compound of Formula (I) as described in the present disclosure in the presence of a CO source.

In some embodiments, the method includes contacting an aryl halide and an alkyne with a compound of Formula (I) as described in the present disclosure in the presence of a CO source. In some embodiments, the aryl halide is a compound having the formula:

wherein:

X is selected from F, Cl, Br, and I; and

R′ is selected from —H, —O—(C₁-C₃ alkyl), —NO₂, and —C(═O)—(C₁-C₃ alkyl).

In some embodiments, X is Br. In some embodiments, X is I.

In some embodiments, R′ is —H. In some embodiments, R′ is —OCH₃. In some embodiments, R′ is —NO₂. In some embodiments, R′ is —C(═O)CH₃.

In some embodiments, the method includes contacting an aryl halide and an alkyne with a compound of Formula (I) as described in the present disclosure in the presence of a CO source. In some embodiments, the alkyne is a compound having the formula:

wherein R″ is selected from —H, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl, —O—(C₁-C₃ alkyl), aryl, (C₁-C₃ alkyl)-(C₃-C₆ cycloalkyl), and (C₁-C₃ alkyl)-aryl. In some embodiments, R″ is —H. In some embodiments, R″ is C₁-C₆ alkyl. In some embodiments, R″ is methyl. In some embodiments, R″ is ethyl. In some embodiments, R″ is propyl. In some embodiments, R″ is butyl. In some embodiments, R″ is tert-butyl. In some embodiments, R″ is pentyl. In some embodiments, R″ is hexyl. In some embodiments, R″ is decyl. In some embodiments, R″ is —OCH₃. In some embodiments, R″ is C₃-C₆ cycloalkyl. In some embodiments, R″ is cyclopropyl. In some embodiments, R″ is cyclobutyl. In some embodiments, R″ is cyclopentyl. In some embodiments, R″ is cyclohexyl. In some embodiments, R″ is aryl. In some embodiments, R″ is —CH₂-cyclohexyl. In some embodiments, R″ is (C₁-C₃ alkyl)-aryl. In some embodiments, R″ is benzyl. In some embodiments, R″ is —(CH₂)₂-aryl. In some embodiments, R″ is —(CH₂)₃-aryl.

In some embodiments, the alkyne is a compound having the formula:

wherein R′″ is selected from —H, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl, —O—(C₁-C₃ alkyl), aryl, (C₁-C₃ alkyl)-(C₃-C₆ cycloalkyl), and (C₁-C₃ alkyl)-aryl. In some embodiments, R″ is —H. In some embodiments, R″ is C₁-C₆ alkyl. In some embodiments, R″ is methyl. In some embodiments, R″ is ethyl. In some embodiments, R″ is propyl. In some embodiments, R″ is butyl. In some embodiments, R″ is tert-butyl. In some embodiments, R″ is pentyl. In some embodiments, R″ is hexyl. In some embodiments, R″ is decyl. In some embodiments, R″ is —OCH₃. In some embodiments, R″ is C₃-C₆ cycloalkyl. In some embodiments, R″ is cyclopropyl. In some embodiments, R″ is cyclobutyl. In some embodiments, R″ is cyclopentyl. In some embodiments, R″ is cyclohexyl. In some embodiments, R″ is aryl. In some embodiments, R″ is —CH₂-cyclohexyl. In some embodiments, R″ is (C₁-C₃ alkyl)-aryl. In some embodiments, R″ is benzyl. In some embodiments, R″ is —(CH₂)₂-aryl. In some embodiments, R″ is —(CH₂)₃-aryl.

In some embodiments of the method of producing an alkynone, the compound of Formula (I) is a compound of Formula (I) of the present disclosure. In some embodiments, the compound of Formula (I) is selected from:

The compounds of Formula (I) have high catalytic efficiency and activity and allow for low catalyst loading. In some embodiments, less than or about 1 mol % of the compound of Formula (I) is required to catalyze a reaction, such as a carbonylative Sonogashira coupling reaction. In some embodiments, the amount of catalyst (compound of Formula (I)) used in the carbonylative Sonogashira coupling reaction is about 0.01 mol % to about 1 mol %, such as about 0.01 mol % to about 0.99 mol %, about 0.01 mol % to about 0.9 mol %, about 0.01 mol % to about 0.8 mol %, about 0.01 mol % to about 0.7 mol %, about 0.01 mol % to about 0.6 mol %, about 0.01 mol % to about 0.5 mol %, about 0.01 mol % to about 0.4 mol %, about 0.01 mol % to about 0.3 mol %, about 0.01 mol % to about 0.2 mol %, about 0.01 mol % to about 0.1 mol %, about 0.01 mol % to about 0.05 mol %, about 0.01 mol % to about 0.03 mol %, about 0.03 mol % to about 1 mol %, 0.03 mol % to about 0.99 mol %, about 0.03 mol % to about 0.9 mol %, about 0.03 mol % to about 0.8 mol %, about 0.03 mol % to about 0.7 mol %, about 0.03 mol % to about 0.6 mol %, about 0.03 mol % to about 0.5 mol %, about 0.03 mol % to about 0.4 mol %, about 0.03 mol % to about 0.3 mol %, about 0.03 mol % to about 0.2 mol %, about 0.03 mol % to about 0.1 mol %, about 0.03 mol % to about 0.05 mol %, about 0.05 mol % to about 1 mol %, 0.05 mol % to about 0.99 mol %, about 0.05 mol % to about 0.9 mol %, about 0.05 mol % to about 0.8 mol %, about 0.05 mol % to about 0.7 mol %, about 0.05 mol % to about 0.6 mol %, about 0.05 mol % to about 0.5 mol %, about 0.05 mol % to about 0.4 mol %, about 0.05 mol % to about 0.3 mol %, about 0.05 mol % to about 0.2 mol %, about 0.05 mol % to about 0.1 mol %, about 0.1 mol % to about 1 mol %, 0.1 mol % to about 0.99 mol %, about 0.1 mol % to about 0.9 mol %, about 0.1 mol % to about 0.8 mol %, about 0.1 mol % to about 0.7 mol %, about 0.1 mol % to about 0.6 mol %, about 0.1 mol % to about 0.5 mol %, about 0.1 mol % to about 0.4 mol %, about 0.1 mol % to about 0.3 mol %, about 0.1 mol % to about 0.2 mol %, about 0.2 mol % to about 1 mol %, 0.2 mol % to about 0.99 mol %, about 0.2 mol % to about 0.9 mol %, about 0.2 mol % to about 0.8 mol %, about 0.2 mol % to about 0.7 mol %, about 0.2 mol % to about 0.6 mol %, about 0.2 mol % to about 0.5 mol %, about 0.2 mol % to about 0.4 mol %, about 0.2 mol % to about 0.3 mol %, about 0.3 mol % to about 1 mol %, 0.3 mol % to about 0.99 mol %, about 0.3 mol % to about 0.9 mol %, about 0.3 mol % to about 0.8 mol %, about 0.3 mol % to about 0.7 mol %, about 0.3 mol % to about 0.6 mol %, about 0.3 mol % to about 0.5 mol %, about 0.3 mol % to about 0.4 mol %, about 0.4 mol % to about 1 mol %, 0.4 mol % to about 0.99 mol %, about 0.4 mol % to about 0.9 mol %, about 0.4 mol % to about 0.8 mol %, about 0.4 mol % to about 0.7 mol %, about 0.4 mol % to about 0.6 mol %, about 0.4 mol % to about 0.5 mol %, about 0.5 mol % to about 1 mol %, 0.5 mol % to about 0.99 mol %, about 0.5 mol % to about 0.9 mol %, about 0.5 mol % to about 0.8 mol %, about 0.5 mol % to about 0.7 mol %, about 0.5 mol % to about 0.6 mol %, about 0.6 mol % to about 1 mol %, 0.6 mol % to about 0.99 mol %, about 0.6 mol % to about 0.9 mol %, about 0.6 mol % to about 0.8 mol %, about 0.6 mol % to about 0.7 mol %, about 0.7 mol % to about 1 mol %, 0.7 mol % to about 0.99 mol %, about 0.7 mol % to about 0.9 mol %, about 0.7 mol % to about 0.8 mol %, about 0.8 mol % to about 1 mol %, 0.8 mol % to about 0.99 mol %, about 0.8 mol % to about 0.9 mol %, about 0.9 mol % to about 1 mol %, 0.9 mol % to about 0.99 mol %, or about 0.01 mol %, about 0.03 mol %, about 0.05 mol %, about 0.1 mol %, about 0.15 mol %, about 0.2 mol %, about 0.25 mol %, about 0.3 mol %, about 0.35 mol %, about 0.4 mol %, about 0.45 mol %, about 0.5 mol %, about 0.55 mol %, about 0.6 mol %, about 0.65 mol %, about 0.7 mol %, about 0.75 mol %, about 0.8 mol %, about 0.85 mol %, about 0.9 mol %, about 0.95 mol %, about 0.99 mol %, or about 1 mol %. In some embodiments, the compound of Formula (I) is present in an amount of about 0.01 mol % to about 1.0 mol %. In some embodiments, the compound of Formula (I) is present in an amount of about 0.01 mol % to about 0.5 mol %. In some embodiments, the compound of Formula (I) is present in an amount of about 0.01 mol % to about 0.05 mol %. In some embodiments, the compound of Formula (I) is present in an amount of about 0.1 mol % to about 0.25 mol %. In some embodiments, the compound of Formula (I) is present in an amount of about 0.03 mol %. In some embodiments, the compound of Formula (I) is present in an amount of about 0.2 mol %. Without wishing to be bound by any particular theory, it is believed that the increased catalytic activity of the compound of Formula (I) allows for the use of smaller amounts of the catalyst as compared to other palladium-based catalysts that have lower catalytic activity. For example, the amount of the compound of Formula (I) can be less than or about 1 mol %, which is less than the amount of about 1 mol % to about 5 mol % required by other palladium-based catalysts with lower catalytic activity.

In some embodiments of the methods of producing alkynones as described in the present disclosure, any suitable CO source can be used. In some embodiments, the CO source is carbon monoxide gas.

The alkynones of the present disclosure have utility as precursors in the synthesis of products such as anti-cancer agents and anti-fungal agents. The alkynones of the present disclosure can also be used in the polymer industry. In some embodiments, the method produces an alkynone having the formula:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the alkynone is a compound having the formula

or a pharmaceutically acceptable salt thereof.

In some embodiments, the alkynone is a compound having the formula

or a pharmaceutically acceptable salt thereof.

EXAMPLES Example 1—Synthesis of palladium(II)-N-heterocyclic carbene-pyridine (Pd—NHC-Py) Complexes

A series of palladium(II)-N-heterocyclic carbene-pyridine (Pd-NHC-Py) complexes (Pd-C1, Pd-C2 and Pd-C3) were prepared in several steps from 1H-benzo[d]imidazole.

Synthesis of alkyl-1H-benzo[d]imidazoles

Alkyl-1H-benzo[d]imidazoles BZ1 and BZ2 were prepared according to Scheme 4.

Briefly, the 1-alkyl benzimidazoles (BZ1 and BZ2) were prepared by the following procedure: Benzimidazole (10.0 mmol) was introduced into a clean and dry round bottom flask with an excess amount of alkyl bromide (12.2 mmol) (2-bromopropane or benzyl bromide). Potassium hydroxide (20.0 mmol) or cesium carbonate (20.0 mmol) with 1 mmol of TBAB (tetrabutylammonium bromide) was used as a base for 2-bromopropane and benzyl bromide, respectively. The mixture was dissolved in 100 mL of distilled acetonitrile and stirred for 24 hrs at 80° C. The reaction was monitored by TLC (1/1: ethyl acetate/hexanes) until no unreacted benzimidazole was observed. The solvent was then removed by a rotary evaporator. The oily product was purified by extraction twice with 30 mL of ethyl acetate and 20 mL of distilled water. The aqueous layer was separated and washed with ethyl acetate and the combined organic layers were dried and washed several times with n-hexane.

1-Isopropyl-1H-benzo[d]imidazole (BZ1)

Yield=77%. Sticky brown oil product. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.85 (s, 1H, N₂CH_(bini)), 7.64-7.62 (m, 1H, Ar—H), 7.25-7.22 (m, 1H, Ar—H), 7.11-7.08 (m, 2H, Ar—H), 4.42 (sep, 1H, ³J=6.76 Hz, NCH) 1.40 (d, 6H, ³J=6.76 Hz, NC(CH₃)₂); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ (ppm): 143.5 (NCN), 139.8, 132.7, 122.1, 121.5, 119.8, 109.7, (Ar—H), 47.2 (NCH), 22.02 [NC(CH₃)₂]. Anal. Calcd for C₁₀H₁₂N₂ (160): C, 74.97%; H, 7.55%; N, 17.48%. Found: C, 74.84%; H, 7.23%; N, 17.93%.

1-Benzyl-1H-benzo[d]imidazole (BZ2)

Yield 87%; light yellow solid; ¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.98 (s, 1H, N₂CH_(bini)), 7.83 (d, 1H, ³J=7.63 Hz, Ar—H), 7.34-7.24 (m, 6H, Ar—H), 7.18 (d, 2H, ³J=7.02 Hz, Ar—H), 5.36 (m, 2H, NCH₂-Ph); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ (ppm); 143.1 (NCN), 135.4, 129, 128.3, 127.06, 123.1, 122.3, 120.3, 110.04 (Ar—H), 48.8 (NCH₂). Anal. Calcd for C₁₄H₁₂N₂ (208.26): C, 80.74%; H, 5.81%; N, 13.45%. Found: C, 80.79%; H, 5.63%; N, 13.58%.

Alkyl-1H-benzo[d]imidazoles BZ3 was prepared according to Scheme 5.

1-Adamantyl benzimidazole (BZ3) was synthesized as follows. 2-Fluoronitrobenzene (10.0 mmol) was added to 1-adamantylamine (14.5 mmol) and anhydrous potassium fluoride (13.3 mmol) under argon in a 50 mL schlenk purged and flamed under vacuum. After 3 vacuum/argon cycles, the mixture was heated, stirred at 180° C. for 48 hrs, and cooled to room temperature. Dichloromethane was added to the reaction mixture followed by the addition of water. The organic phase was washed with brine and water, followed by drying on sodium sulfate and concentrated under vacuum. The crude mixture was purified on silica gel using a dichloromethane/hexane mixture (2/10) affording a yellow-orange solid (0.178 g, 92%) of ortho-nitro-1-adamantylaniline. The reduction of ortho-nitro-1-adamantylaniline was achieved using sodium borohydride to produce ortho-aminoadamantyl aniline. The reduction process started by dissolving 10.0 mmol of ortho-nitro-1-adamantylaniline in THF and then 0.250 mmol of Pd/C was added carefully. The resulting slurry was stirred and NaBH4 (25.0 mmol) was added portion-wise. The obtained solid was then filtered and extracted three times using a mixture of ethyl acetate and H2O. To fully dry the solid, anhydrous sodium sulfate was added and the solid filtered off and evaporated to dryness to yield ortho-aminoadamantyl aniline (76%) as a dark oil. Finally, a round-bottom flask was charged with ortho-aminoadamantyl aniline (8.80 mmol), anhydrous tetrahydrofuran (THF), trimethyl orthoformate (6.60 mmol) and formic acid (0.880 mmol). The mixture was stirred overnight at room temperature. Solvents were evaporated and the crude product was purified by chromatography to yield the N-adamantyl-1H-benzo[d]imidazole (BZ3) (85%).

1-(adamantan-1-yl)-1H-benzo[d]imidazole (BZ3)

Yield 85%; light brown solid; NMR (500 MHz, DMSO-d⁶) δ (ppm): 8.22 (s, 1H, N₂CH_(bini)), 7.85 (m, 1H, Ar—H), 7.64 (m, 1H, Ar—H), 7.18 (m, 2H, Ar—H), 2.33 (m, 6H, 3CH₂), 2.21 (m, 3H, 3CH), 1.81-1.75 (m, 6H, NC 3CH₂); ¹³C{¹H} NMR (125 MHz, DMSO-d6) δ (ppm); 140.8 (NCN), 121.6, 121.1, 119.8, 113.9 (Ar—H), 56.6 (NC), 41.13 NC(C)₃, 35.45 C(CH)CH₂, 28.98 CH(CH₂)CH. Anal. Calcd for C₁₇H₂₀N₂ (252.36): C, 80.91%; H, 7.99%; N, 11.10%. Found: C, 80.73%; H, 7.76%; N, 11.51%.

Synthesis of NHC Ligand Precursors

NHC ligand precursors NHC-1, NHC-2, and NHC-3 were prepared from BZ1, BZ2, and BZ3, respectively, as shown in Scheme 6.

NHC-1, NHC-2, and NHC-3 were prepared by charging the appropriate 1-alkyl benzimidazole (BZ1, BZ2, or BZ3) (1.00 mmol) and 2-bromopropane (3.00 mL) into a pressure tube. The mixture was stirred for 48 hours at 120° C. and then cooled down to room temperature. For NHC-1 and NHC-3 cases, the filtration was used to collect the products as solid precipitates and then washed several times with diethyl ether (5 mL). The pure product was dried under vacuum. For NHC-2, a brown sticky mixture was obtained. Based on the ionic nature of the product, a careful extraction under a fume hood with 5 mL of water (three times) was carried out. The aqueous layer was collected, and water was evaporated under vacuum. The product was obtained as orange crystals.

1,3-Diisopropylbenzimidazole-3-ium Bromide (NHC-1)

Yield=65%. White solid. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 11.35 (s, 1H, N₂CH_(bini)), 7.80-7.78 (m, 2H, C—H-arom), 7.65-7.63 (m, 2H, C—H arom), 5.19 (sep, 2H, ³J=6.8 Hz, NCH), 1.85 (d, 12H, ³J=6.8 Hz, 2(CH₃)₂); ¹³C NMR (125 MHz, CDCl₃) δ (ppm): 140.69, 130.85, 126.89, 113.90 (C arom); 52.39 2C(CH₃)₂, 22.24, 2(CH₃)₂, GC-MS m/z 283.2 (M^(t)). Anal. Calc. for C₁₃H₁BrN₂, (283.21): C, 55.13%; H, 6.76%; N, 9.89%. Found: C, 55.41; H, 7.02; N, 10.03. ESI-MS: m/z 202.17 [M-Br]⁺.

1-Benzyl-3-isopropyl-1H-benzo[d]imidazol-3-ium Bromide (NHC-2)

Yield=85%.

Orange crystalline solid. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 11.51 (s, 1H, N₂C—H_(bini)), 7.78 (d, 1H, ³J=8.00 Hz, C—H arom), 7.65-7.51 (m, 5H, C—H arom), 7.35-7.29 (m, 3H, C—H-(aryl)), 5.97 (s, 2H, CH₂-Ph), 5.03 (sep, 1H, ³J=6.4 Hz, NCH), 1.83 (d, 6H, ³J=6.4 Hz, NC(CH₃)₂); ¹³C NMR (125 MHz, CDCl₃) δ (ppm): 141.31, 132.99, 131.51, 130.77, 129.27, 129.10, 128.52, 127.26, 127.14, 114.08, 113.64 (C arom), 51.95 (NCH₂), 51.37 (NCH₂), 22.44 (2(CH₃)₂). Anal. Calc. for C₁₇H₁₉BrN₂, (331.26): C, 61.64%; H, 5.78%; N, 8.46%. Found: C, 62.051; H, 5.93; N, 8.80. MS: m/z 331.2 (M^(t)). ESI-MS; m/z 251.2 [M−Br]⁺.

1-(Adamantan-1-yl)-3-isopropyl-1H-benzo[d]imidazol-3-ium Bromide (NHC-3)

Yield=88%. Light brown solid. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.82 (s, 1H, N₂C—H_(bini)), 8.03 (d, 1H, ³J=8 Hz, C—H arom), 7.2 (d, 1H, J=7.0 Hz, C—H arom), 7.63-7.57 (m, 2H, C—H arom), 5.61 (sep, 1H, ³J=6.4 Hz, CH), 2.55 (m, 6H, 3CH_(2adam)), 2.41 (m, 3H, 3CH_(Adam)), 1.87-1.85 (m, 12H, {3CH_(2Adam)}+{2CH₃}); ¹³C NMR (125 MHz, CDCl₃) δ (ppm): 140.22, 131.44, 130.49, 126.31, 126.04, 116.77, 114.59 (C arom), 63.02 NC(C)₃, 52.86 C(CH₃)₂ 41.72 C(CH₂)₃, 35.58 3(CH), 29.54 [3(CH₂), C(CH₃)₂]. Anal. Calc. for C₂₀H₂₇BrN₂, (375.35): C, 64.00%; H, 7.25%; N, 7.46%. Found: C, 64.321; H, 7.53; N, 7.80. MS: m/z 375 (M^(t)); ESI-MS; m/z 294.2 [M-Br]⁺.

Synthesis of palladium(II)-NHC-pyridine Complexes

Pd-NHC-Py complexes Pd-1, Pd-2, and Pd-3 were prepared from NHC-1, NHC-2, and NHC-3, respectively, as shown in Scheme 7.

Pd-C1, Pd-C2, and Pd-C3 were prepared by reacting palladium bromide with 1.0 equivalent of the appropriate ligand precursor (NHC-1, NHC-2 and NHC-3) and an excess amount of pyridine. Briefly, a round bottom flask (15 mL) was charged with the appropriate N-heterocyclic carbene ligand precursor (NHC-1, NHC-2, or NHC-3) (0.50 mmol), palladium (II) bromide (0.50 mmol), potassium carbonate (2.0 mmol) and pyridine (5 mL). The reaction mixture was heated to 90° C. for 24 hrs under stirring. After cooling down to room temperature, the colloidal crude product was diluted with 5 mL of dichloromethane and the mixture was purified by passing through a short silica column covered with a short pad of Celite. The flash column was eluted with distilled methanol. The solvents were evaporated using rotary evaporator. The complexes were washed with ether, collected and dried at room temperature under vacuum. The complexes were obtained as yellow crystals. A slow crystallization procedure was followed in the preparation of single crystals for these complexes. A saturated solution of the palladium was prepared in dichloromethane/acetonitrile (8/1) (v/v). The disappearance of the acidic C-2 protons of the benzimidazole rings, which were initially present in the N-substituted imidazolium salts, was used to confirm the formation of the Pd-NHC complexes. The appearance of new signals at 156-158 ppm in the ¹³C NMR spectra of the three complexes assignable to the palladated carbon Pd-C was a further indication of the palladation of the NHC ligand precursors.

(1,3-Diisopropyl-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)(pyridin-1(2H)-yl)palladium(II) Bromide (Pd-C1)

Yield=77%. Yellow solid. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.07-9.06 (m, 2H, C—H-pyr), 7.73-7.70 (m, 1H, C—H-pyr), 7.53-7.52 (m, 2H, C—H arom), 7.31-7.29 (m, 2H, C—H arom), 7.16-7.15 (m, 2H, C—H pyr), 6.27 (sep, 2H, ³J=7.2 Hz, NCH), 1.73 (d, 12H, ³J=7.2 Hz, 4CH₃), ¹³C NMR (125 MHz, CDCl₃) δ (ppm): 158.14 (Pd-C), 151.56, 136.71, 132.31, 123.34, 121.04, 111.43 (C arom); 53.38 [C(CH₃)₂], 19.41 (2CH₃). Calc. for C₁₈H₂₃Br₂N₃Pd, (547.63): C, 39.48%; H, 4.23%; N, 7.67%. Found: C, 40.05; H, 4.62; N, 7.94. ESI-MS: m/z 467.12 [M−Br]⁺.

(1-Benzyl-3-isopropyl-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)(pyridin-1(2H)-yl)palladium(II) Bromide (Pd-C2)

Yield=74%. Yellow crystals. ¹H NMR (400 MHz, CDCl₃) δ (ppm): ¹H NMR (400 MHz, CDCl₃) δ (ppm): δ (ppm): 9.06-9.05 (m, 2H, C—H pyr), 7.71-7.69 (m, 1H, C—H pyr), 7.48 (m, 2H, C—H arom), 7.45-7.41 (m, 5H, C—H arom), 7.35-7.29 (m, 2H, C—H aryl), 7.13-7.09 (m, 3H, C—H pyr), 5.87 (s, 1H, CH₂-Ph), 5.30 (m, 1H, NCH), 1.67 (m, 6H, NC(CH₃)₂); ¹³C NMR (125 MHz, CDCl₃) δ (ppm): 154.34 (Pd-C), 153.4, 138.51, 128.82, 128.12, 127.26, 127.14, 125.04, 122.78, 112.33, 110.69 (C arom), 53.47 (NCH₂), 51.37 (NCH₂), 21.44 [(CH₃)₂]. Anal. Calc. for C₂₂H₂₃Br₂N₃Pd, (595.68): C, 44.36%; H, 3.39%; N, 7.05%. Found: C, 43.85; H, 4.13; N, 7.48; ESI-MS: m/z 515.11 [M−Br]⁺.

(1-(Adamantan-1-yl)-3-isopropyl-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)(pyridin-1(2H)-yl)palladium(II) Bromide (Pd-C3)

Yield=86%. Light yellow crystals. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.11-9.10 (m, 2H, C—H pyr), 8.87 (d, 1H, ³J=7.8 Hz, C—H arom), 7.81-7.77 (m, 1H, C—H pyr), 7.64 (d, 1H, ³J=7.4 Hz, C—H arom), 7.39-7.36 (m, 2H, C—H arom), 7.25-7.18 (m, 2H, C—H-pyr), 7.11 (sep, 1H, ³J=7 Hz, NCH), 3.24 (m, 6H, 3CH_(2Adam)), 2.43 (m, 3H, 3CH_(Adam)), 1.98 (m, 3H, 3CH_(Adam)), 1.85-1.83 (m, 9H, {3CH_(Adam)+2CH₃); ¹³C NMR (125 MHz, CDCl₃) δ (ppm): 156.78 (Pd-C), 152.95, 137.78, 135.03, 133.17, 124.64, 122.04, 121.33, 115.71, 112.72 (C arom), 61.78 NC(C)₃, 57.16 C(CH₃)₂ 42.61 C(CH₂)₃, 36.17 3(CH), 30.26 3(CH₂), 20.24 C(CH₃)₂. Anal. Calc. for C₂₅H₃₁Br₂N₃Pd, (639.77): C, 46.93%; H, 4.88%; N, 6.57%. Found: C, 47.32; H, 5.33; N, 7.13. ESI-MS: m/z 559.09 [M−Br]⁺.

Example 2—Carbonylative Sonogashira Coupling Reactions

The palladium(II)-N-heterocyclic carbene-pyridine (Pd-NHC-Py) complexes Pd-C1, Pd-C2 and Pd-C3 prepared according to Example 1 were used in carbonylative Sonogashira coupling reactions to produce alkynones. The Pd-NHC-Py catalysts displayed high catalytic activity with low catalyst loading. The reactions required only 0.03 mol % of the Pd-NHC-Py complex and produced alkynones in high yield.

Synthesis of Aryl Alkynones Using Pd-C1, Pd-C2, and Pd-C3

An aryl alkynone was synthesized by reacting 4-iodoanisole (1.0 mmol) with arylacetylene (1.5 mmol) in the presence of 0.03 mol % catalyst Pd-C1, Pd-C2, or Pd-C3, Et3N (2.0 mmol), and CO (200 psi) in toluene (3 mL) at 100° C. for 3 hours, as shown in Scheme 8 and Table 1.

TABLE 1 Isolated Yield NHC—Pd—Py 3aa Entry (mol %) (%) 1 Pd—C1 85 (0.03) 2 Pd—C2 79 (0.03) 3 Pd—C3 97 (0.03)

Synthesis of Aryl Alkynones Using Pd-C3

A series of aryl alkynones was synthesized by reacting aryl iodides with functionalized aryl alkynes in the presence of the Pd-C3 catalyst as shown in Scheme 9 and Table 2.

TABLE 2 Aryl Aryl Alkyne Carbonylative Isolated Entry Iodide 1 2 Sonogashira 3 Yield (%) 1 1a

97 2 1a

94 3 1a

96 4 1b

98 5 1c

95

The carbonylative coupling reaction was performed by reacting aryl iodides 1a-1c with functionalized aryl alkynes 2a-2c in the presence of 0.03 mol % of Pd-C3, with 2.0 equivalents of Et3N, 3 mL of toluene, 200 psi CO, at 100° C. for 3 hrs. Alkynones 3a-3e were produced in excellent yields (94-98%) via the carbonylative Sonogashira coupling reaction.

Synthesis of Alkyl Alkynones Using Pd-C3

A series of alkyl alkynones was synthesized by reacting aryl iodides with alkyl alkynes in the presence of the Pd-C3 catalyst as shown in Scheme 10.

The carbonylative coupling reaction was performed by reacting aryl iodides 1a-1d with alkyl alkynes 4a-4h in the presence of 0.20 mol % of Pd-C3, with 2.0 equivalents of Et3N, 3 mL of toluene, 200 psi CO, at 100° C. for 18 hrs. Alkynones 5a-5i were produced in high yields (67-95%) via the carbonylative Sonogashira coupling reaction as shown in Table 3.

TABLE 3 Aryl Alkyl Isolated Iodide Alkyne Product Yield la-d 4a-h 5ba-da (%) 1b

89 1b

92 1b

95 1a

87 1a

94 1a

67 1c^(a)

93 1c^(a)

76

96 ^(a)Time = 6 hrs.

Other Embodiments

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. 

What is claimed is:
 1. A compound of Formula (I)

wherein: R¹, R², and R³ are each independently selected from C₁-C₁₀ alkyl, C₅-C₁₀ cycloalkyl, aryl, and (C₁-C₃ alkylene)-aryl, with the proviso that R¹ and R² are different when ring A is pyridine; n is 0, 1, 2, 3, 4, or 5; m is 1 or 2; and

represents a single or double bond.
 2. The compound of claim 1, wherein R¹ is C₁-C₆ alkyl.
 3. The compound of claim 2, wherein R¹ is selected from methyl, ethyl, propyl, isopropyl, and butyl.
 4. The compound of claim 3, wherein R¹ is isopropyl.
 5. The compound of claim 1, wherein R² is selected from C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, and (C₁-C₃ alkylene)-aryl.
 6. The compound of claim 5, wherein R² is selected from isopropyl, benzyl, and adamantyl.
 7. The compound of claim 1, wherein n is
 0. 8. The compound of claim 1, wherein m is
 2. 9. The compound of claim 8, wherein ring A is


10. The compound of claim 1, wherein the compound of Formula (I) is selected from:


11. A compound of Formula (II)

wherein: R¹ and R² are each independently selected from C₁-C₁₀alkyl, C₅-C₁₀ cycloalkyl, aryl, and (C₁-C₃ alkylene)-aryl, with the proviso that R¹ and R² are different; and X is a halide.
 12. The compound of claim 11, wherein R¹ is C₁-C₆ alkyl.
 13. The compound of claim 12, wherein R¹ is selected from methyl, ethyl, propyl, isopropyl, and butyl.
 14. The compound of claim 13, wherein R¹ is isopropyl.
 15. The compound of claim 11, wherein R² is selected from C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, and (C₁-C₃ alkylene)-aryl.
 16. The compound of claim 15, wherein R² is selected from isopropyl, benzyl, and adamantyl.
 17. The compound of claim 11, wherein the compound of Formula (II) is selected from:


18. A method of preparing a compound of Formula (I)

the method comprising reacting a compound of Formula (II)

with pyridine in the presence of a palladium catalyst, wherein: R¹ and R² are each independently selected from C₁-C₁₀ alkyl, C₅-C₁₀ cycloalkyl, aryl, and (C₁-C₃ alkylene)-aryl, with the proviso that R¹ and R² are different.
 19. The method of claim 18, wherein R¹ is isopropyl.
 20. The method of claim 18, wherein R² is selected from isopropyl, benzyl, and adamantyl.
 21. The method of claim 18, wherein the compound of Formula (I) is selected from:


22. The method of claim 18, wherein the palladium catalyst is palladium bromide.
 23. A method of preparing an alkynone, comprising contacting an aryl halide and an alkyne with a compound of Formula (I) according to claim 1 in the presence of a CO source.
 24. The method of claim 23, wherein the aryl halide is a compound having the formula:

wherein: X is selected from F, Cl, Br, and I; and R′ is selected from —H, —O—(C₁-C₃ alkyl), —NO₂, and —C(═O)—(C1-C₃ alkyl).
 25. The method of claim 24, wherein X is I.
 26. The method of claim 23, wherein the alkyne is a compound having the formula:

wherein R″ is selected from —H, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl, —O—(C₁-C₃ alkyl), aryl, (C₁-C₃ alkyl)-(C₃-C₆ cycloalkyl), and (C₁-C₃ alkyl)-aryl.
 27. The method of claim 23, wherein the alkyne is a compound having the formula:

wherein R′″ is selected from —H, C₁-C₁₀ alkyl, C₃-C₆ cycloalkyl, —O—(C₁-C₃ alkyl), aryl, (C₁-C₃ alkyl)-(C₃-C₆ cycloalkyl), and (C₁-C₃ alkyl)-aryl.
 28. The method of claim 23, wherein the alkynone is a compound having the formula:

or a pharmaceutically acceptable salt thereof.
 29. The method of claim 23, wherein the compound of Formula (I) is selected from:


30. The method of claim 23, wherein the compound of Formula (I) is present in an amount of about 0.01 mol % to about 1.0 mol %. 